Current health care modalities for humans diagnosed with either precancerous actinic keratoses or skin cancers (including basal and squamous cell carcinomas) primarily involve surgical excision of the lesions or chemical or photodynamic burning of the affected tissues. These post-diagnostic treatments are directed to disease management, while disease prevention strategies focus on public education that advocates for limiting sunlight exposures, especially in the first two decades of life. However, with ~1.4 million new cases of skin cancer diagnosed in the United States each year, additional prevention strategies are needed. To address this need, Restoration Genetics, Inc (RGI) has developed and patented technologies activating a second, nuclear- targeted DNA repair pathway, base excision repair, for the removal of the primary DNA lesions caused by sunlight exposure, cyclobutane pyrimidine dimers (CPDs). Using Phase I STTR funding, RGI successfully demonstrated the purification of the critical repair enzyme, chlorella virus pyrimidine dimer DNA glycosylase (Cv-pdg-NLS, RG-101), encapsulation of the enzyme into liposomes, and the successful initiation of rapid repair of CPDs in a human skin model. Building from these data, in collaboration with Oregon Health &Science University, RGI will carry out a series of preclinical studies including cGMP process development, biological efficacy analyses, and commercialization development, all of which culminate in a pre-IND meeting with the FDA. Specifically, RG-101 will be produced and packaged in a large-scale cGMP facility at the University of Nebraska and RG-101 encapsulated in liposomes will be tested for preclinical biological efficacy to 1) activate repair of solar-simulated light in a human skin model, 2) prevent UV-induced carcinogenesis in a rodent model, and 3) reduce tumor frequencies following an initial tumor diagnosis. Additionally, pharmacokinetic and toxicology studies will be designed using rabbit and pig models. These investigations complement well the commercialization plan that targets three markets: 1) individuals who are deficient in the normal DNA repair mechanism for CPD removal (conducted under Orphan Drug Status), 2) organ transplant patients who are highly susceptible to frequent, highly aggressive skin cancers, and 3) individuals with high frequency actinic keratoses and cancers, as well as the general public. Collectively, the data will be presented to the FDA in a pre-IND meeting for guidance in pharmacology and toxicology trials and Phase I human clinical trials. Specifically, in this meeting we will present manufacturing, characterization and encapsulation data, biochemical activities of the enzyme and in vitro efficacy in fully differentiated human skin models, mouse carcinogenesis data, and the design of animal pharmacology and toxicology assessments. PUBLIC HEALTH RELEVANCE: Acute and chronic exposures to sunlight are the primary risk factors for the development of skin cancer. Human cells possess only one mechanism for the repair of UV-induced DNA damage. Our laboratories have patented new enzymes that activate a second DNA repair pathway. Thus, our technology will augment and dramatically improve human DNA repair capacity for removal of sunlight-induced damage. The anticipated societal benefits are to significantly reduce the number and average age of onset of new skin cancers.